The overall goal of proposal is to develop novel therapies for improvement of long-term outcomes of renal and cardiac transplants in high and low risk recipients. 1. Cardiac Transplantation: We will test the hypothesis that B cells, by promoting indirect T cell alloreactivity and humoral alloimmunity, play a critical role in development of chronic allograft vasculopathy (CAV). We propose a multicenter, randomized, and placebo controlled trial where 300 primary heart transplant recipients with a PRA of <10% will be randomized to conventional immunosuppression (tacrolimus, MMF and rapid steroid taper) versus induction therapy with anti-CD20 mAb (Rituxan) plus conventional immunosuppression. The primary endpoint is development of CAV by IVUS at one year post-transplant. This trial will be conducted in collaboration with Dr. Peter Heeger who will also be proposing a separate second pilot cardiac trail to desensitize highly sensitized recipients from the same cardiac consortium. 2. Kidney Transplantation: 2A. We will test the hypothesis that interruption of B cell maturation by TACI-lg (a fusion protein antagonist of BAFF and APRIL) will reduce acute rejection rates and improve outcome in highly sensitized renal transplant recipients. We propose a multicenter, randomized, and placebo controlled trial in highly sensitized (PRA >50%) deceased or live donor renal transplant recipients that have undergone a desensitization protocol and/or received a negative cross- matched kidney. We will enroll 200 subjects randomized into two groups. All patients will receive thymoglobulin and tacrolimus, MMF, and steroids. The experimental group will also be treated with TACI-lg. The primary endpoint will be biopsy-proven acute rejection rates (cellular/antibody mediated) at 1 year post- transplant. Recipients will be followed for 24 months to determine impact of therapy on long-term outcome. 2B. We will test the hypothesis that strategies that limit effector/memory T cell alloreactivity and expand regulatory T cells in vivo will allow minimization of immunosuppression to a single agent in low risk renal transplant recipients. We propose a pilot safety and feasibility study with initial induction with thymoglobulin followed by monthly injections (x4) of low dose thymoglobulin at months 2-5 post-transplant, LEA29Y (belatacept) and MMF. A control group will receive thymoglobulin induction plus tacrolimus, MMF and rapid steroid taper. We plan to enroll 48 subjects with 3:1 randomization in the therapeutic and control arms, respectively. The primary end point is percentage of CD4+CD25+FOXP3+ Tregs in the peripheral blood at 6 months post-transplant. Based on specific clinical criteria recipients in the experimental arm will then undergo withdrawal of MMF starting at 1 year post-transplant. 3. All subjects in all three trials will be followed with extensive mechanistic studies to test the overall hypothesis that the interventional therapeutic protocols described above are associated with measurable changes in the phenotype of T cells (effector/memory and Tregs), T cell alloreactivity against donor alloantigen, humoral alloimmunity, phenotypic differentiation of T and B cells, as well as molecular mediators of acute and chronic allograft dysfunction. We will test specific hypotheses and assays tailored to the relevant clinical protocol in cardiac and renal transplant recipients with the goal of understanding the immunobiology and mechanisms of therapy, and to ultimately develop novel biomarkers to predict short- and long-term outcomes in these recipients. Relevance: As required by the RFA we propose novel therapeutic strategies in two different groups of organ transplant recipients, kidney and heart, accompanied by extensive mechanistic studies to better understand the immunobiology of the specific disease process, the mechanisms of action of our therapeutic interventions, as well as develop novel biomarkers. Our studies have major implications for improving outcomes of solid organ transplant recipients.